1. Field of the Invention
The present invention relates to compounds effective as catalysts for dismutating superoxide and, more particularly, relates to manganese or iron complexes of nitrogen-containing fifteen-membered macrocyclic ligands which catalytically dismutate superoxide.
2. Related Art
The enzyme superoxide dismutase catalyzes the conversion of superoxide into oxygen and hydrogen peroxide according to equation (1) (hereinafter referred to as dismutation). Reactive oxygen metabolites derived from superoxide are postulated to contribute to the tissue pathology in a number of
O2xe2x88x92+O2xe2x88x92+2H+xe2x86x92O2+H2O2xe2x80x83xe2x80x83(1)
inflammatory diseases and disorders, such as reperfusion injury to the ischemic myocardium, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, atherosclerosis, hypertension, metastasis, psoriasis, organ transplant rejections, radiation-induced injury, asthma, influenza, stroke, burns and trauma. See, for example, Bulkley, G. B., Reactive oxygen metabolites and reperfusion injury: aberrant triggering of reticuloendothelial function, The Lancet, Vol. 344, pp. 934-36, Oct. 1, 1994; Grisham, M. B., Oxidants and free radicals in inflammatory bowel disease, The Lancet, Vol. 344, pp. 859-861, Sep. 24, 1994; Cross, C. E. et al., Reactive oxygen species and the lung, The Lancet, Vol. 344, pp. 930-33, Oct. 1, 1994; Jenner, P., Oxidative damage in neurodegenerative disease, The Lancet, Vol. 344, pp. 796-798, Sep. 17, 1994; Cerutti, P. A., Oxy-radicals and cancer, The Lancet, Vol. 344, pp. 862-863, Sep. 24, 1994 Simic, M. G., et al, Oxygen Radicals in Biology and Medicine, Basic Life Sciences, Vol. 49, Plenum Press, New York and London, 1988; Weiss J. Cell. Biochem., 1991 Suppl. 15C, 216 Abstract C110 (1991); Petkau, A., Cancer Treat. Rev. 13, 17 (1986); McCord, J. Free Radicals Biol. Med., 2, 307 (1986); and Bannister, J. V. et al, Crit. Rev. Biochem., 22, 111 (1987). The above-identified references from The Lancet teach the nexus between free radicals derived from superoxide and a variety of diseases. In particular, the Bulkley and Grisham references specifically teach that there is a nexus between the dismutation of superoxide and the final disease treatment.
It is also known that superoxide is involved in the breakdown of endothelium-derived vascular relaxing factor (EDRF), which has been identified as nitric oxide (NO), and that EDRF is protected from breakdown by superoxide dismutase. This suggests a central role for activated oxygen species derived from superoxide in the pathogenesis of vasospasm, thrombosis and atherosclerosis. See, for example, Gryglewski, R. J. et al., xe2x80x9cSuperoxide Anion is Involved in the Breakdown of Endothelium-derived Vascular Relaxing Factorxe2x80x9d, Nature, Vol. 320, pp. 454-56 (1986) and Palmer, R. M. J. et al., xe2x80x9cNitric Oxide Release Accounts for the Biological Activity of Endothelium Derived Relaxing Factorxe2x80x9d, Nature, Vol. 327, pp. 523-26 (1987).
Clinical trials and animal studies with natural, recombinant and modified superoxide dismutase enzymes have been completed or are ongoing to demonstrate the therapeutic efficacy of reducing superoxide levels in the disease states noted above. However, numerous problems have arisen with the use of the enzymes as potential therapeutic agents, including lack of oral activity, short half-lives in vivo, immunogenicity with nonhuman derived enzymes, and poor tissue distribution.
It is an object of the invention to provide manganese or iron complexes of nitrogen-containing fifteen-membered macrocyclic ligands that are low molecular weight mimics of superoxide dismutase (SOD) which are useful as therapeutic agents for inflammatory disease states or disorders which are mediated, at least in part, by superoxide. It is a further object of the invention to provide manganese (II) or iron (III) complexes of nitrogen-containing fifteen-membered macrocyclic ligands which are useful as magnetic resonance imaging (MRI) contrast agents having improved kinetic stability, improved oxidative stability and improved hydrogen bonding. It is yet a further object of the invention to provide MRI contrast agents in which the biodistribution of the contrast agents can be controlled.
According to the invention, manganese or iron complexes of nitrogen-containing fifteen-membered macrocyclic ligands are provided in which at least one adjacent pair of carbon atoms in the macrocyclic ligand are substituted with alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl radicals wherein at least one of the substituents on the adjacent carbons is substituted with xe2x80x94OR10, xe2x80x94NR10R11, xe2x80x94COR10, xe2x80x94CO2R10, xe2x80x94CONR10R11, xe2x80x94Oxe2x80x94(xe2x80x94(CH2)axe2x80x94O)bxe2x80x94R10, xe2x80x94SR10, xe2x80x94SOR10, xe2x80x94SO2R10, xe2x80x94SO2NR10R11, xe2x80x94N(OR10)(R11), xe2x80x94P(O)(OR10)(OR11), xe2x80x94P(O)(OR10)(R11) and xe2x80x94OP(O)(OR10)(OR11) wherein R10 and R11 are independently selected from hydrogen or alkyl groups, and a and b are integers independently selected from 1 to 6.
The present invention is directed to manganese or iron complexes of nitrogen-containing fifteen-membered macrocyclic ligands which catalyze the conversion of superoxide into oxygen and hydrogen peroxide. These complexes can be represented by the formula: 
wherein at least one pair of xe2x80x9cRxe2x80x9d groups on adjacent carbon atoms of the macrocycle selected from the group consisting of R9 or Rxe2x80x29 and R or Rxe2x80x2, R1 or Rxe2x80x21 and R2 or Rxe2x80x22, R3 or Rxe2x80x23 and R4 or Rxe2x80x24, R5 or Rxe2x80x25 and R6 or Rxe2x80x26, and R7 or Rxe2x80x27 and R8 or Rxe2x80x28 are substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl or substituted cycloalkenyl radicals wherein the substituents are independently selected from the group consisting of xe2x80x94OR10, xe2x80x94NR10R11, xe2x80x94COR10, xe2x80x94CO2R10, xe2x80x94CONR10R11, xe2x80x94Oxe2x80x94(xe2x80x94(CH2)axe2x80x94O)bxe2x80x94R10, xe2x80x94SR10, xe2x80x94SOR10, xe2x80x94SO2R10, xe2x80x94SO2NR10R11, xe2x80x94N(OR10)(R11), xe2x80x94P(O)(OR10)(OR11), xe2x80x94P(O)(OR10)(R11) and xe2x80x94OP(O)(OR10)(OR11); or at least one pair of xe2x80x9cRxe2x80x9d groups on adjacent carbon atoms of the macrocycle selected from the group consisting of R9 or Rxe2x80x29 and R or Rxe2x80x2, R1 or Rxe2x80x21 and R2 or Rxe2x80x22, R3 or Rxe2x80x23 and R4 or Rxe2x80x24, R5 or Rxe2x80x25 and R6 or Rxe2x80x26, and R7 or Rxe2x80x27and R8 or Rxe2x80x28 are independently selected wherein one xe2x80x9cRxe2x80x9d group of the pair is an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl radical and the other xe2x80x9cRxe2x80x9d group on the adjacent carbon atom of the macrocycle is a substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl or substituted cycloalkenyl radical wherein the substituents are independently selected from the group consisting of xe2x80x94OR10, xe2x80x94NR10R11, xe2x80x94COR10, xe2x80x94CO2R10, xe2x80x94CONR10R11, xe2x80x94Oxe2x80x94(xe2x80x94(CH2)axe2x80x94O)bxe2x80x94R10, xe2x80x94SR10, xe2x80x94SOR10, xe2x80x94SO2R10, xe2x80x94SO2NR10R11, xe2x80x94N(OR10)(R11), xe2x80x94P(O)(OR10)(OR11), xe2x80x94P(O)(OR10)(R11) and xe2x80x94OP(O)(OR10)(OR11); or combinations thereof; wherein R10 and R11 are independently selected from the group consisting of hydrogen and alkyl groups, and a and b are integers independently selected from 1 to 6; and the remaining xe2x80x9cRxe2x80x9d groups are hydrogen or, optionally, are independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkylcycloalkenyl, alkenylcycloalkenyl, heterocyclic, aryl and aralkyl radicals and radicals attached to the xcex1-carbon of xcex1-amino acids; or R1 or Rxe2x80x21 and R2 or Rxe2x80x22, R3 or Rxe2x80x23 and R4 or Rxe2x80x24, R5 or Rxe2x80x25 and R6 or Rxe2x80x26, R7 or Rxe2x80x27 and R8 or Rxe2x80x28, and R9 or Rxe2x80x29 and R or Rxe2x80x2 together with the carbon atoms to which they are attached independently form a saturated, partially saturated or unsaturated cyclic having 3 to 20 carbon atoms; or R or Rxe2x80x2 and R1 or Rxe2x80x21, R2 or Rxe2x80x22 and R3 or Rxe2x80x23, R4 or Rxe2x80x24 and R5 or Rxe2x80x25, R6 or Rxe2x80x26 and R7 or Rxe2x80x27, and R8 or Rxe2x80x28 and R9 or Rxe2x80x29 together with the carbon atoms to which they are attached independently form a nitrogen containing heterocycle having 2 to 20 carbon atoms provided that when the nitrogen containing heterocycle is an aromatic heterocycle which does not contain a hydrogen attached to the nitrogen, the hydrogen attached to the nitrogen in said formula, which nitrogen is also in the macrocycle and the R groups attached to the same carbon atoms of the macrocycle are absent; and combinations thereof; wherein M is Mn or Fe.
The currently preferred optional xe2x80x9cRxe2x80x9d groups are alkyl radicals, radicals attached to the xcex1-carbon of xcex1-amino acids, and saturated, partially saturated or unsaturated cyclic ring structures having 3 to 20 carbon atoms. Currently, R10 and R11 are preferably hydrogen.
X, Y and Z represent suitable ligands or charge-neutralizing anions which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof (for example benzoic acid or benzoate anion, phenol or phenoxide anion, alcohol or alkoxide anion). X, Y and Z are independently selected from the group consisting of halide, oxo, aquo, hydroxo, alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino, heterocycloalkyl amino, heterocycloaryl amino, amine oxides, hydrazine, alkyl hydrazine, aryl hydrazine, nitric oxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkyl nitrile, aryl nitrile, alkyl isonitrile, aryl isonitrile, nitrate, nitrite, azido, alkyl sulfonic acid, aryl sulfonic acid, alkyl sulfoxide, aryl sulfoxide, alkyl aryl sulfoxide, alkyl sulfenic acid, aryl sulfenic acid, alkyl sulfinic acid, aryl sulfinic acid, alkyl thiol carboxylic acid, aryl thiol carboxylic acid, alkyl thiol thiocarboxylic acid, aryl thiol thiocarboxylic acid, alkyl carboxylic acid (such as acetic acid, trifluoroacetic acid, oxalic acid), aryl carboxylic acid (such as benzoic acid, phthalic acid), urea, alkyl urea, aryl urea, alkyl aryl urea, thiourea, alkyl thiourea, aryl thiourea,alkyl aryl thiourea, sulfate, sulfite, bisulfate, bisulfite, thiosulfate, thiosulfite, hydrosulfite, alkyl phosphine, aryl phosphine, alkyl phosphine oxide, aryl phosphine oxide, alkyl aryl phosphine oxide, alkyl phosphine sulfide, aryl phosphine sulfide, alkyl aryl phosphine sulfide, alkyl phosphonic acid, aryl phosphonic acid, alkyl phosphinic acid, aryl phosphinic acid, alkyl phosphinous acid, aryl phosphinous acid, phosphate, thiophosphate, phosphite, pyrophosphite, triphosphate, hydrogen phosphate, dihydrogen phosphate, alkyl guanidino, aryl guanidino, alkyl aryl guanidino, alkyl carbamate, aryl carbamate, alkyl aryl carbamate, alkyl thiocarbamate aryl thiocarbamate, alkyl aryl thiocarbamate, alkyl dithiocarbamate, aryl dithiocarbamate, alkyl aryl dithiocarbamate, bicarbonate, carbonate, perchlorate, chlorate, chlorite, hypochlorite, perbromate, bromate, bromite, hypobromite, tetrahalomanganate, tetrafluoroborate, hexafluorophosphate, hexafluoroantimonate, hypophosphite, iodate, periodate, metaborate, tetraaryl borate, tetra alkyl borate, tartrate, salicylate, succinate, citrate, ascorbate, saccharinate, amino acid, hydroxamic acid, thiotosylate, and anions of ion exchange resins, or systems where one or more of X,Y and Z are independently attached to one or more of the xe2x80x9cRxe2x80x9d groups, wherein n is 0 or 1. The preferred ligands from which X, Y and Z are selected include halide, organic acid, nitrate and bicarbonate anions.
Currently, the preferred compounds are those wherein at least one pair of xe2x80x9cRxe2x80x9d groups on adjacent carbon atoms of the macrocycle selected from the group consisting of R9 or Rxe2x80x29 and R or Rxe2x80x2, R1 or Rxe2x80x21 and R2 or Rxe2x80x22, R3 or Rxe2x80x23 and R4 or Rxe2x80x24, R5 or Rxe2x80x25 and R6 or Rxe2x80x26, and R7 or Rxe2x80x27and R8 or Rxe2x80x28 are substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl or substituted cycloalkenyl radicals wherein the substituents are independently selected from the group consisting of xe2x80x94OR10, xe2x80x94NR10R11, xe2x80x94COR10, xe2x80x94CO2R10, xe2x80x94CONR10R11, xe2x80x94Oxe2x80x94(xe2x80x94(CH2)axe2x80x94O)bxe2x80x94R10, xe2x80x94SR10, xe2x80x94SOR10, xe2x80x94SO2R10, xe2x80x94SO2NR10R11, xe2x80x94N(OR10)(R11), xe2x80x94P(O)(OR10)(OR11), xe2x80x94P(O)(OR10)(R11) and xe2x80x94OP(O)(OR10)(OR11), more preferably xe2x80x94OR10 or xe2x80x94NR10R11, and most preferably xe2x80x94OR10 and the remaining xe2x80x9cRxe2x80x9d groups are hydrogen or, optionally, are independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkylcycloalkenyl, alkenylcycloalkenyl, heterocyclic, aryl and aralkyl radicals and radicals attached to the xcex1-carbon of xcex1-amino acids; or R1 or Rxe2x80x21 and R2 or Rxe2x80x22, R3 or Rxe2x80x23 and R4 or Rxe2x80x24, R5 or Rxe2x80x25 and R6 or Rxe2x80x26, R7 or Rxe2x80x27 and R8 or Rxe2x80x28, and R9 or Rxe2x80x29 and R or Rxe2x80x2 together with the carbon atoms to which they are attached independently form a saturated, partially saturated or unsaturated cyclic having 3 to 20 carbon atoms; or R or Rxe2x80x2 and R1 or Rxe2x80x21, R2 or Rxe2x80x22 and R3 or Rxe2x80x23, R4 or Rxe2x80x24 and R5 or Rxe2x80x25, R6 or Rxe2x80x26 and R7 or Rxe2x80x27, and R8 or Rxe2x80x28 and R9 or Rxe2x80x29 together with the carbon atoms to which they are attached independently form a nitrogen containing heterocycle having 2 to 20 carbon atoms provided that when the nitrogen containing heterocycle is an aromatic heterocycle which does not contain a hydrogen attached to the nitrogen, the hydrogen attached to the nitrogen in said formula, which nitrogen is also in the macrocycle and the R groups attached to the same carbon atoms of the macrocycle are absent; and combinations thereof. Even more preferred are compounds wherein the xe2x80x9cRxe2x80x9d groups of the at least one pair of xe2x80x9cRxe2x80x9d groups on adjacent carbon atoms of the macrocycle are substituted alkyl groups, and the substituents are preferably xe2x80x94OR10 and more preferably xe2x80x94OH.
Another preferred group of compounds are those wherein at least one pair of xe2x80x9cRxe2x80x9d groups on adjacent carbon atoms of the macrocycle selected from the group consisting of R9 or Rxe2x80x29 and R or Rxe2x80x2, R1 or Rxe2x80x21 and R2 or Rxe2x80x22, R3 or Rxe2x80x23 and R4 or Rxe2x80x24, R5 or Rxe2x80x25 and R6 or Rxe2x80x26, and R7 or Rxe2x80x27 and R8 or Rxe2x80x28 are independently selected wherein one xe2x80x9cRxe2x80x9d group of the pair is an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl radical and the other xe2x80x9cRxe2x80x9d group on the adjacent carbon atom of the macrocycle is a substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl or substituted cycloalkenyl radical wherein the substituents are independently selected from the group consisting of xe2x80x94OR10, xe2x80x94NR10R11, xe2x80x94COR10, xe2x80x94CO2R10, xe2x80x94CONR10R11, xe2x80x94Oxe2x80x94(xe2x80x94(CH2)axe2x80x94O)bxe2x80x94R10, xe2x80x94SR10, xe2x80x94SOR10, xe2x80x94SO2R10, xe2x80x94SO2NR10R11, xe2x80x94N(OR10)(R11), xe2x80x94P(O)(OR10)(OR11), xe2x80x94P(O)(OR10)(R11) and xe2x80x94OP(O)(OR10)(OR11), more preferably xe2x80x94OR10 or xe2x80x94NR10R11, and most preferably xe2x80x94OR10; and the remaining xe2x80x9cRxe2x80x9d groups are hydrogen or, optionally, are independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkylcycloalkenyl, alkenylcycloalkenyl, heterocyclic, aryl and aralkyl radicals and radicals attached to the xcex1-carbon of xcex1-amino acids; or R1 or Rxe2x80x21 and R2 or Rxe2x80x22, R3 or Rxe2x80x23 and R4 or Rxe2x80x24, R5 or Rxe2x80x25 and R6 or Rxe2x80x26, R7 or Rxe2x80x27 and R8 or Rxe2x80x28, and R9 or Rxe2x80x29 and R or Rxe2x80x2 together with the carbon atoms to which they are attached independently form a saturated, partially saturated or unsaturated cyclic having 3 to 20 carbon atoms; or R or Rxe2x80x2 and R1 or Rxe2x80x21, R2 or Rxe2x80x22 and R3 or Rxe2x80x23, R4 or Rxe2x80x24 and R5 or Rxe2x80x25, R6 or Rxe2x80x26 and R7 or Rxe2x80x27, and R8 or Rxe2x80x28 and R9 or Rxe2x80x29 together with the carbon atoms to which they are attached independently form a nitrogen containing heterocycle having 2 to 20 carbon atoms provided that when the nitrogen containing heterocycle is an aromatic heterocycle which does not contain a hydrogen attached to the nitrogen, the hydrogen attached to the nitrogen in said formula, which nitrogen is also in the macrocycle and the R groups attached to the same carbon atoms of the macrocycle are absent; and combinations thereof. Even more preferred are compounds wherein one xe2x80x9cRxe2x80x9d group of the at least one pair of xe2x80x9cRxe2x80x9d groups on adjacent carbon atoms of the macrocycle is an alkyl group and the other xe2x80x9cRxe2x80x9d group on the adjacent carbon atom of the macrocycle is a substituted alkyl group, and the substituent on the carbon atom of the at least one pair of xe2x80x9cRxe2x80x9d groups on adjacent carbon atoms of the macrocycle which is a substituted group is xe2x80x94OR10, and more preferably xe2x80x94OH.
As used herein, xe2x80x9cRxe2x80x9d groups means all of the R groups attached to the carbon atoms of the macrocycle, i.e., R, Rxe2x80x2, R1, Rxe2x80x21, R2 , Rxe2x80x22, R3, Rxe2x80x23, R4, Rxe2x80x24, R5, Rxe2x80x25, R6, Rxe2x80x26, R7, Rxe2x80x27, R8, Rxe2x80x28, R9. Examples of complexes of the invention include, but are not limited to, compounds having the formulas: 
Another embodiment of the invention is a pharmaceutical composition in unit dosage form useful for dismutating superoxide comprising (a) a therapeutically or prophylactically effective amount of a complex as described above and (b) a nontoxic, pharmaceutically acceptable carrier, adjuvant or vehicle.
A further embodiment of the invention is the macrocyclic ligands represented by the formula: 
wherein the xe2x80x9cRxe2x80x9d groups are as defined above.
The commonly accepted mechanism of action of the manganese-based SOD enzymes involves the cycling of the manganese center between the two oxidation states (II,III). See J. V. Bannister, W. H. Bannister, and G. Rotilio, Crit. Rev. Biochem., 22, 111-180 (1987).
Mn(II)+HO2.xe2x86x92Mn(III)+HO2xe2x80x83xe2x80x83(1)
Mn(III)+O2.xe2x86x92Mn(II)+O2xe2x80x83xe2x80x83(2)
The formal redox potentials for the O2/O2.xe2x80x94 and HO2/H2O2 couples at pH=7 are xe2x88x920.33 v and 0.87 v, respectively. See A. E. G. Cass, in Metalloproteins: Part 1, Metal Proteins with Redox Roles, ed. P. Harrison, P. 121. Verlag Chemie (Weinheim, GDR) (1985). For the above disclosed mechanism, these potentials require that a putative SOD catalyst be able to rapidly undergo oxidation state changes in the range of xe2x88x920.33 v to 0.87 v.
The complexes derived from Mn(II) and the general class of C-substituted [15]aneN5 ligands described herein have been characterized using cyclic voltammetry to measure their redox potential. The manganese-based C-substituted complexes described herein have reversible oxidations of about +0.7 v (SHE). Coulometry shows that this oxidation is a one-electron process; namely it is the oxidation of the Mn(II) complex to the Mn(III) complex. Thus, for these complexes to function as SOD catalysts, the Mn(III) oxidation state is involved in the catalytic cycle. This means that the Mn(III) complexes of all these ligands are equally competent as SOD catalysts, since it does not matter which form (Mn(II) or Mn(III)) is present when superoxide is present because superoxide will simply reduce Mn(III) to Mn(II) liberating oxygen.
The iron-based complexes of the invention are particularly useful due to the unexpectedly enhanced stability of the iron-based complexes compared to the corresponding manganese-based complexes. The enhanced stability could be important in oral administration and where targeted tissue has very low pH, e.g. ischemic tissue.
As utilized herein, the term xe2x80x9calkylxe2x80x9d, alone or in combination, means a straight-chain or branched-chain alkyl radical containing from 1 to about 22 carbon atoms, preferably from about 1 to about 18 carbon atoms, and most preferably from about 1 to about 12 carbon atoms which optionally carries one or more substituents selected from (1) xe2x80x94NR30R31 wherein R30 and R31 are independently selected from hydrogen, alkyl, aryl or aralkyl; or R30is hydrogen, alkyl, aryl or aralkyl and R31 is selected from the group consisting of xe2x80x94NR32R33, xe2x80x94OH, xe2x80x94OR34, 
wherein R32 and R33 are independently hydrogen, alkyl, aryl or acyl, R34 is alkyl, aryl or alkaryl, Zxe2x80x2 is hydrogen, alkyl, aryl, alkaryl, xe2x80x94OR34, xe2x80x94SR34 or xe2x80x94NR40R41 wherein R40 and R41 are independently selected from hydrogen, alkyl, aryl or alkaryl, Zxe2x80x3 is alkyl, aryl, alkaryl, xe2x80x94OR34, xe2x80x94SR34 or xe2x80x94NR40R41, R35 is alkyl, aryl, xe2x80x94OR34, or xe2x80x94NR40R41, R36 is alkyl, aryl or xe2x80x94NR40R41, R37 is alkyl, aryl or alkaryl, Xxe2x80x2 is oxygen or sulfur, and R38 and R39 are independently selected from hydrogen, alkyl or aryl; (2) xe2x80x94SR42 wherein R42 is hydrogen, alkyl, aryl, alkaryl, xe2x80x94SR34, xe2x80x94NR32R33, 
wherein R43 is xe2x80x94OH, xe2x80x94OR34 or xe2x80x94NR32R33, and A and B are independently xe2x80x94OR34, xe2x80x94SR34 or xe2x80x94NR32R33; 
wherein x is 1 or 2, and R44 is alkyl, aryl, alkaryl, xe2x80x94OH, xe2x80x94OR34, xe2x80x94SR34 or xe2x80x94NR32R33; (4) xe2x80x94OR45 wherein R45 is hydrogen, alkyl, aryl, alkaryl, xe2x80x94NR32R33, 
wherein D and E are independently xe2x80x94OR34 or xe2x80x94NR32R33; 
wherein R46 is xe2x80x94OH, xe2x80x94SH, xe2x80x94OR34, xe2x80x94SR34 or xe2x80x94NR32R33; or
(6) amine oxides of the formula 
provided R30 and R31 are not hydrogen; or 
wherein F and G are independently xe2x80x94OH, xe2x80x94SH, xe2x80x94OR34, xe2x80x94SR34 or xe2x80x94NR32R33; or (8) halogen, cyano, nitro, or azido. Alkyl, aryl and alkaryl groups on the substituents of the above-defined alkyl groups may contain one additional substituent but are preferably unsubstituted. Examples of such radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl and eicosyl. The term xe2x80x9calkenylxe2x80x9d, alone or in combination, means an alkyl radical having one or more double bonds. Examples of such alkenyl radicals include, but are not limited to, ethenyl, propenyl, 1-butenyl, cis-2-butenyl, trans-2-butenyl, iso-butylenyl, cis-2-pentenyl, trans-2-pentenyl, 3-methyl-1-butenyl, 2,3-dimethyl-2-butenyl, 1-pentenyl, 1-hexenyl, 1-octenyl, decenyl, dodecenyl, tetradecenyl, hexadecenyl, cis- and trans-9-octadecenyl, 1,3-pentadienyl, 2,4-pentadienyl, 2,3-pentadienyl, 1,3-hexadienyl, 2,4-hexadienyl, 5,8,11,14-eicosatetraenyl, and 9,12,15-octadecatrienyl. The term xe2x80x9calkynylxe2x80x9d, alone or in combination, means an alkyl radical having one or more triple bonds. Examples of such alkynyl groups include, but are not limited to, ethynyl, propynyl (propargyl), 1-butynyl, 1-octynyl, 9-octadecynyl, 1,3-pentadiynyl, 2,4-pentadiynyl, 1,3-hexadiynyl, and 2,4-hexadiynyl. The term xe2x80x9ccycloalkylxe2x80x9d, alone or in combination means a cycloalkyl radical containing from 3 to about 10, preferably from 3 to about 8, and most preferably from 3 to about 6, carbon atoms. Examples of such cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and perhydronaphthyl. The term xe2x80x9ccycloalkylalkylxe2x80x9d means an alkyl radical as defined above which is substituted by a cycloalkyl radical as defined above. Examples of cycloalkylalkyl radicals include, but are not limited to, cyclohexylmethyl, cyclopentylmethyl, (4-isopropylcyclohexyl)methyl, (4-t-butyl-cyclohexyl)methyl, 3-cyclohexylpropyl, 2-cyclo-hexylmethylpentyl, 3-cyclopentylmethylhexyl, 1-(4-neopentylcyclohexyl)methylhexyl, and 1-(4-isopropylcyclohexyl)methylheptyl. The term xe2x80x9ccycloalkylcycloalkylxe2x80x9d means a cycloalkyl radical as defined above which is substituted by another cycloalkyl radical as defined above. Examples of cycloalkylcycloalkyl radicals include, but are not limited to, cyclohexylcyclopentyl and cyclohexylcyclohexyl. The term xe2x80x9ccycloalkenylxe2x80x9d, alone or in combination, means a cycloalkyl radical having one or more double bonds. Examples of cycloalkenyl radicals include, but are not limited to, cyclopentenyl, cyclohexenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl and cyclooctadienyl. The term xe2x80x9ccycloalkenylalkylxe2x80x9d means an alkyl radical as defined above which is substituted by a cycloalkenyl radical as defined above. Examples of cycloalkenylalkyl radicals include, but are not limited to, 2-cyclohexen-1-ylmethyl, 1-cyclopenten-1-ylmethyl, 2-(1-cyclohexen-1-yl)ethyl, 3-(1-cyclopenten-1-yl)propyl, 1-(1-cyclohexen-1-ylmethyl)pentyl, 1-(1-cyclopenten-1-yl)hexyl, 6-(1-cyclohexen-1-yl)hexyl, 1-(1-cyclopenten-1-yl)nonyl and 1-(1-cyclohexen-1-yl)nonyl. The terms xe2x80x9calkylcycloalkylxe2x80x9d and xe2x80x9calkenylcycloalkylxe2x80x9d mean a cycloalkyl radical as defined above which is substituted by an alkyl or alkenyl radical as defined above. Examples of alkylcycloalkyl and alkenylcycloalkyl radicals include, but are not limited to, 2-ethylcyclobutyl, 1-methylcyclopentyl, 1-hexylcyclopentyl, 1-methylcyclohexyl, 1-(9-octadecenyl)cyclopentyl and 1-(9-octadecenyl)cyclohexyl. The terms xe2x80x9calkylcycloalkenylxe2x80x9d and xe2x80x9calkenylcycloalkenylxe2x80x9d means a cycloalkenyl radical as defined above which is substituted by an alkyl or alkenyl radical as defined above. Examples of alkylcycloalkenyl and alkenylcycloalkenyl radicals include, but are not limited to, 1-methyl-2-cyclopentyl, 1-hexyl-2-cyclopentenyl, l-ethyl-2-cyclohexenyl, 1-butyl-2-cyclohexenyl, 1-(9-octadecenyl)-2-cyclohexenyl and 1-(2-pentenyl)-2-cyclohexenyl. The term xe2x80x9carylxe2x80x9d, alone or in combination, means a phenyl or naphthyl radical which optionally carries one or more substituents selected from alkyl, cycloalkyl, cycloalkenyl, aryl, heterocycle, alkoxyaryl, alkaryl, alkoxy, halogen, hydroxy, amine, cyano, nitro, alkylthio, phenoxy, ether, trifluoromethyl and the like, such as phenyl, p-tolyl, 4-methoxyphenyl, 4-(tert-butoxy)phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, 1-naphthyl, 2-naphthyl, and the like. The term xe2x80x9caralkylxe2x80x9d, alone or in combination, means an alkyl or cycloalkyl radical as defined above in which one hydrogen atom is replaced by an aryl radical as defined above, such as benzyl, 2-phenylethyl, and the like. The term xe2x80x9cheterocyclicxe2x80x9d means ring structures containing at least one other kind of atom, in addition to carbon, in the ring. The most common of the other kinds of atoms include nitrogen, oxygen and sulfur. Examples of heterocyclics include, but are not limited to, pyrrolidinyl, piperidyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, furyl, thienyl, pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrazinyl, indolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridinyl, benzoxadiazolyl, benzothiadiazolyl, triazolyl and tetrazolyl groups. The term xe2x80x9csaturated, partially saturated or unsaturated cyclicxe2x80x9d means fused ring structures in which 2 carbons of the ring are also part of the fifteen-membered macrocyclic ligand. The ring structure can contain 3 to 20 carbon atoms, preferably 5 to 10 carbon atoms, and can also contain one or more other kinds of atoms in addition to carbon. The most common of the other kinds of atoms include nitrogen, oxygen and sulfur. The ring structure can also contain more than one ring. The term xe2x80x9csaturated, partially saturated or unsaturated ring structurexe2x80x9d means a ring structure in which one carbon of the ring is also part of the fifteen-membered macrocyclic ligand. The ring structure can contain 3 to 20, preferably 5 to 10, carbon atoms and can also contain nitrogen, oxygen and/or sulfur atoms. The term xe2x80x9cnitrogen containing heterocyclexe2x80x9d means ring structures in which 2 carbons and a nitrogen of the ring are also part of the fifteen-membered macrocyclic ligand. The ring structure can contain 2 to 20, preferably 4 to 10, carbon atoms, can be partially or fully unsaturated or saturated and can also contain nitrogen, oxygen and/or sulfur atoms in the portion of the ring which is not also part of the fifteen-membered macrocyclic ligand. The term xe2x80x9corganic acid anionxe2x80x9d refers to carboxylic acid anions having from about 1 to about 18 carbon atoms. The term xe2x80x9chalidexe2x80x9d means chloride or bromide.
The macrocyclic ligands useful in the complexes of the present invention can also be prepared according to the general procedure shown in Scheme A set forth below. Thus, an amino acid amide, which is the corresponding amide derivative of a naturally or non-naturally occurring xcex1-amino acid, is reduced to form the corresponding substituted ethylenediamine. Such amino acid amide can be the amide derivative of any one of many well known amino acids. Preferred amino acid amides are those represented by the formula: 
wherein R is derived from the D or L forms of the amino acids Alanine, Aspartic acid, Arginine, Asparagine, Cysteine, Glycine, Glutamic acid, Glutamine, Histidine, Isoleucine, Leucine, Lysine, Methionine, Proline, Phenylalanine, Serine, Tryptophan, Threonine, Tyrosine, Valine and/or the R groups of unnatural xcex1-amino acids such as alkyl, ethyl, butyl, tert-butyl, cycloalkyl, phenyl, alkenyl, allyl, alkynyl, aryl, heteroaryl, polycycloalkyl, polycycloaryl, polycycloheteroaryl, imines, aminoalkyl, hydroxyalkyl, hydroxyl, phenol, amine oxides, thioalkyl, carboalkoxyalkyl, carboxylic acids and their derivatives, keto, ether, aldehyde, amine, nitrile, halo, thiol, sulfoxide, sulfone, sulfonic acid, sulfide, disulfide, phosphonic acid, phosphinic acid, phosphine oxides, sulfonamides, amides, amino acids, peptides, proteins, carbohydrates, nucleic acids, fatty acids, lipids, nitro, hydroxylamines, hydroxamic acids, thiocarbonyls, borates, boranes, boraza, silyl, siloxy, silaza, and combinations thereof. Most preferred are those wherein R represents hydrogen, alkyl, cycloalkylalkyl, and aralkyl radicals. The diamine is then tosylated to produce the di-N-tosyl derivative which is reacted with a di-o-tosylated tris-N-tosylated triazaalkane diol to produce the corresponding substituted N-pentatosylpentaazacycloalkane. The tosyl groups are then removed and the resulting compound is reacted with a manganese(II) or iron (III) compound under essentially anhydrous and anaerobic conditions to form the corresponding substituted manganese(II) or iron (III) pentaazacycloalkane complex. When the ligands or charge-neutralizing anions, i.e. X, Y and Z, are anions or ligands that cannot be introduced directly from the manganese or iron compound, the complex with those anions or ligands can be formed by conducting an exchange reaction with a complex that has been prepared by reacting the macrocycle with a manganese or iron compound.
The complexes of the present invention, wherein R9, and R2 are alkyl, and R3, Rxe2x80x23, R4, Rxe2x80x24, R5, Rxe2x80x25, R6, Rxe2x80x26, R7, Rxe2x80x27, R8 and Rxe2x80x28 can be alkyl, arylalkyl or cycloalkylalkyl and R or Rxe2x80x2 and R1 or Rxe2x80x21 together with the carbon atoms they are attached to are bound to form a nitrogen containing heterocycle, can also be prepared according to the general procedure shown in Scheme B set forth below utilizing methods known in the art for preparing the manganese(II) or iron (III) pentaazabicyclo[12.3.1]octadecapentaene complex precursor. See, for example, Alexander et al., Inorg. Nucl. Chem. Lett., 6, 445 (1970). Thus a 2,6-diketopyridine is condensed with triethylene tetraamine in the presence of a manganese(II) or iron (III) compound to produce the manganese(II) or iron (III) pentaazabicyclo[12.3.1]octadecapentaene complex. manganese(II) or iron (III) pentaazabicyclo[12.3.1]octadecapentaene complex is hydrogenated with platinum oxide at a pressure of 10-1000 psi to give the corresponding manganese(II) or iron (III) pentaazabicyclo[12.3.1]octadecatriene complex.
The macrocyclic ligands useful in the complexes of the present invention can also be prepared by the diacid dichloride route shown in Scheme C set forth below. Thus, a triazaalkane is tosylated in a suitable solvent system to produce the corresponding tris (N-tosyl) derivative. Such a derivative is treated with a suitable base to produce the corresponding disulfonamide anion. The disulfonamide anion is dialkylated with a suitable electrophile to produce a derivative of a dicarboxylic acid. This derivative of a dicarboxylic acid is treated to produce the dicarboxylic acid, which is then treated with a suitable reagent to form the diacid dichloride. The desired vicinal diamine is obtained in any of several ways. One way which is useful is the preparation from an aldehyde by reaction with cyanide in the presence of ammonium chloride followed by treatment with acid to produce the alpha ammonium nitrile. The latter compound is reduced in the presence of acid and then treated with a suitable base to produce the vicinal diamine. Condensation of the diacid dichloride with the vicinal diamine in the presence of a suitable base forms the tris(tosyl)diamide macrocycle. The tosyl groups are removed and the amides are reduced and the resulting compound is reacted with a manganese (II) or iron (III) compound under essentially anhydrous and anaerobic conditions to form the corresponding substituted pentaazacycloalkane manganese (II) or iron (III) complex.
The vicinal diamines have been prepared by the route shown (known as the Strecker synthesis) and vicinal diamines were purchased when commercially available. Any method of vicinal diamine preparation could be used.
The macrocyclic ligands useful in the complexes of the present invention can also be prepared by the pyridine diamide route shown in Scheme D as set forth below. Thus, a polyamine, such as a tetraaza compound, containing two primary amines is condensed with dimethyl 2,6-pyridine dicarboxylate by heating in an appropriate solvent, e.g., methanol, to produce a macrocycle incorporating the pyridine ring as the 2,6-dicarboxamide. The pyridine ring in the macrocycle is reduced to the corresponding piperidine ring in the macrocycle, and then the diamides are reduced and the resulting compound is reacted with a manganese (II) or iron (III) compound under essentially anhydrous and anaerobic conditions to form the corresponding substituted pentaazacycloalkane manganese (II) or iron (III) complex.
The macrocyclic ligands useful in the complexes of the present invention can also be prepared by the bis(haloacetamide) route shown in Scheme E set forth below. Thus a triazaalkane is tosylated in a suitable solvent system to produce the corresponding tris (N-tosyl) derivative. Such a derivative is treated with a suitable base to produce the corresponding disulfonamide anion. A bis(haloacetamide), e.g., a bis(chloroacetamide), of a vicinal diamine is prepared by reaction of the diamine with an excess of haloacetyl halide, e.g., chloroacetyl chloride, in the presence of a base. The disulfonamide anion of the tris(N-tosyl) triazaalkane is then reacted with the bis(chloroacetamide) of the diamine to produce the substituted tris(N-tosyl)diamide macrocycle. The tosyl groups are removed and the amides are reduced and the resulting compound is reacted with a manganese (II) or iron (III) compound under essentially anhydrous and anaerobic conditions to form the corresponding substituted pentaazacycloalkane manganese (II) or iron (III) complex.
The macrocyclic ligands useful in the complexes of the present invention, wherein R1, Rxe2x80x21, R2, Rxe2x80x22 are derived from a diamino starting material and R5, Rxe2x80x25, R7, Rxe2x80x27 and R9, Rxe2x80x29 can be H or any functionality previously described, can be prepared according to the pseudo-peptide method shown in Scheme F set forth below. A substituted 1,2-diaminoethane represented by the formula 
wherein R1, Rxe2x80x21, R2 and Rxe2x80x22 are the substituents on adjacent carbon atoms in the product macrocyclic ligand as set forth above, can be used in this method in combination with any amino acids. The diamine can be produced by any conventional method known to those skilled in the art. The R groups in the macrocycle derived from substituents on the xcex1-carbon of xcex1-amino acids, i.e. R5, Rxe2x80x25, R7, Rxe2x80x27, R9 and Rxe2x80x29, could be derived from the D or L forms of the amino acids Alanine, Aspartic acid, Arginine, Asparagine, Cysteine, Glycine, Glutamic acid, Glutamine, Histidine, Isoleucine, Leucine, Lysine, Methionine, Proline, Phenylalanine, Serine, Tryptophan, Threonine, Tyrosine, Valine and/or the R groups of unnatural xcex1-amino acids such as alkyl, ethyl, butyl, tert-butyl, cycloalkyl, phenyl, alkenyl, allyl, alkynyl, aryl, heteroaryl, polycycloalkyl, polycycloaryl, polycycloheteroaryl, imines, aminoalkyl, hydroxyalkyl, hydroxyl, phenol, amine oxides, thioalkyl, carboalkoxyalkyl, carboxylic acids and their derivatives, keto, ether, aldehyde, amine, nitrile, halo, thiol, sulfoxide, sulfone, sulfonic acid, sulfide, disulfide, phosphonic acid, phosphinic acid, phosphine oxides, sulfonamides, amides, amino acids, peptides, proteins, carbohydrates, nucleic acids, fatty acids, lipids, nitro, hydroxylamines, hydroxamic acids, thiocarbonyls, borates, boranes, boraza, silyl, siloxy, silaza, and combinations thereof. As an example 1,8-dihydroxy, 4,5-diaminooctane is monotosylated and reacted with Boc anhydride to afford the differentiated N-Boc, N-tosyl derivative. The sulfonamide was alkylated with methyl bromoacetate using sodium hydride as the base and saponified to the free acid. The diamine containing N-tosylglycine serves as a dipeptide surrogate in standard solution-phase peptide synthesis. Thus, coupling with a functionalized amino acid ester affords the corresponding pseudo-tripeptide. Two sequential TFA cleavage-couplings affords the pseudo-pentapeptide which can be N- and C-terminus deprotected in one step using HCl/AcOH. DPPA mediated cyclization followed by LiAlH4or Borane reduction affords the corresponding macrocylic ligand. This ligand system is reacted with a manganese (II) or iron (III) compound, such as manganese (II) chloride or iron (III) chloride, under essentially anaerobic conditions to form the corresponding functionalized manganese (II) or iron (III) pentaazacycloalkane complex. When the ligands or charge-neutralizing anions, i.e. X, Y and Z, are anions or ligands that cannot be introduced directly from the manganese or iron compound, the complex with those anions or ligands can be formed by conducting an exchange reaction with a complex that has been prepared by reacting the macrocycle with a manganese or iron compound.
The following schemes are depicted for preparing the manganese complexes of the invention. The iron complexes of the invention can be prepared by substituting an iron compound for the manganese compound used. 
The pentaazamacrocycles of the present invention can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or nonracemic mixtures thereof. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example by formation of diastereoisomeric salts by treatment with an optically active acid. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts. A different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers. Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting one or more secondary amine group(s) of the compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure ligand. The optically active compounds of the invention can likewise be obtained by utilizing optically active starting materials, such as natural amino acids.
The compounds or complexes of the present invention are novel and can be utilized to treat numerous inflammatory disease states and disorders. For example, reperfusion injury to an ischemic organ, e.g., reperfusion injury to the ischemic myocardium, surgically-induced ischemia, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, psoriasis, organ transplant rejections, radiation-induced injury, oxidant-induced tissue injuries and damage, atherosclerosis, thrombosis, platelet aggregation, stroke, acute pancreatitis, insulin-dependent diabetes mellitus, disseminated intravascular coagulation, fatty embolism, adult and infantile respiratory distress, metastasis and carcinogenesis.
Activity of the compounds or complexes of the present invention for catalyzing the dismutation of superoxide can be demonstrated using the stopped-flow kinetic analysis technique as described in Riley, D.P., Rivers, W. J. and Weiss, R. H., xe2x80x9cStopped-Flow Kinetic Analysis for Monitoring Superoxide Decay in Aqueous Systems,xe2x80x9d Anal. Biochem., 196, 344-349 (1991), which is incorporated by reference herein. Stopped-flow kinetic analysis is an accurate and direct method for quantitatively monitoring the decay rates of superoxide in water. The stopped-flow kinetic analysis is suitable for screening compounds for SOD activity and catalytic activity of the compounds or complexes of the present invention for dismutating superoxide, as shown by stopped-flow analysis, correlate to treating the above disease states and disorders.
Total daily dose administered to a host in single or divided doses may be in amounts, for example, from about 1 to about 100 mg/kg body weight daily and more usually about 3 to 30 mg/kg. Unit dosage compositions may contain such amounts of submultiples thereof to make up the daily dose.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
The dosage regimen for treating a disease condition with the compounds and/or compositions of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized and whether the compound is administered as part of a drug combination. Thus, the dosage regimen actually employed may vary widely and therefore may deviate from the preferred dosage regimen set forth above.
The compounds of the present invention may be administered orally, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders, granules and gels. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds which are known to be effective against the specific disease state that one is targeting for treatment.
The compounds or complexes of the invention can also be utilized as MRI contrast agents. A discussion of the use of contrast agents in MRI can be found in patent application Ser. No. 08/397,469, which is incorporated by reference herein.
Contemplated equivalents of the general formulas set forth above for the compounds and derivatives as well as the intermediates are compounds otherwise corresponding thereto and having the same general properties such as tautomers of the compounds and such as wherein one or more of the various R groups are simple variations of the substituents as defined therein, e.g., wherein R is a higher alkyl group than that indicated, or where the tosyl groups are other nitrogen or oxygen protecting groups or wherein the O-tosyl is a halide. Anions having a charge other than 1, e.g., carbonate, phosphate, and hydrogen phosphate, can be used instead of anions having a charge of 1, so long as they do not adversely affect the overall activity of the complex. However, using anions having a charge other than 1 will result in a slight modification of the general formula for the complex set forth above. In addition, where a substituent is designated as, or can be, a hydrogen, the exact chemical nature of a substituent which is other than hydrogen at that position, e.g., a hydrocarbyl radical or a halogen, hydroxy, amino and the like functional group, is not critical so long as it does not adversely affect the overall activity and/or synthesis procedure. Further, it is contemplated that manganese(III) and iron (II) complexes will be equivalent to the subject manganese(II) and iron (III) complexes.
The chemical reactions described above are generally disclosed in terms of their broadest application to the preparation of the compounds of this invention. occasionally, the reactions may not be applicable as described to each compound included within the disclosed scope. The compounds for which this occurs will be readily recognized by those skilled in the art. In all such cases, either the reactions can be successfully performed by conventional modifications known to those skilled in the art, e.g., by appropriate protection of interfering groups, by changing to alternative conventional reagents, by routine modification of reaction conditions, and the like, or other reactions disclosed herein or otherwise conventional, will be applicable to the preparation of the corresponding compounds of this invention. In all preparative methods, all starting materials are known or readily preparable from known starting materials.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.